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PubMed2000

Repression of the putative tumor suppressor gene Bard1 or expression of Notch4(int-3) oncogene subvert the morphogenetic properties of mammary epithelial cells.

We have investigated whether repression of the putative tumor suppressor gene BARD1 or expression of the Notch4(int-3) oncogene in non-tumorigenic mammary epithelial cells affects their in vitro morphogenetic properties. Bard1 (Brca1-associated ring domain) is a protein interacting with Brca1 and thought to be involved in Brca1-mediated tumor suppression. To investigate the potential role of Bard1 in mammary gland development, we repressed its expression in TAC-2 cells, a murine mammary epithelial cell line which, when grown in three-dimensional collagen gels, forms branching ducts in response to hepatocyte growth factor (HGF) and alveolar-like cysts in response to hydrocortisone. Whereas Bard1 repression did not markedly modify the tubulogenic response of TAC-2 cells to HGF, it dramatically altered cyst development, resulting in the formation of compact cell aggregates devoid of central lumen. In addition, when grown to post-confluence in two-dimensional cultures, Bard1-suppressed TAC-2 cells overcame contact-inhibition of cell proliferation and formed multiple cell layers. The Notch4(int-3) oncogene, which codes for a constitutively activated form of the Notch4 receptor, has been reported to induce undifferentiated carcinomas when expressed in the mammary gland. The potential effect of activated Notch4 on mammary gland morphogenesis was investigated by retroviral expression of the oncogene in TAC-2 cells. Notch4(int-3) expression was found to significantly reduce HGF-induced tubulogenesis and to markedly inhibit hydrocortisone-induced cyst formation. In addition, Notch4(int-3) expressing TAC-2 cells formed multilayers in post-confluent cultures and exhibited an invasive behavior when grown on the surface of collagen gels. Taken together, these results indicate that both repression of Bard1 and expression of Notch4(int-3) disrupt cyst morphogenesis and induce an invasive phenotype in TAC-2 mammary epithelial cells.

Breast↗
PubMed1993

Functional conservation of a glucose-repressible amylase gene promoter from Drosophila virilis in Drosophila melanogaster.

Previous studies have demonstrated that the expression of the alpha-amylase gene is repressed by dietary glucose in Drosophila melanogaster. Here, we show that the alpha-amylase gene of a distantly related species, D. virilis, is also subject to glucose repression. Moreover, the cloned amylase gene of D. virilis is shown to be glucose repressible when it is transiently expressed in D. melanogaster larvae. This cross-species, functional conservation is mediated by a 330-bp promoter region of the D. virilis amylase gene. These results indicate that the promoter elements required for glucose repression are conserved between distantly related Drosophila species. A sequence comparison between the amylase genes of D. virilis and D. melanogaster shows that the promoter sequences diverge to a much greater degree than the coding sequences. The amylase promoters of the two species do, however, share small clusters of sequence similarity, suggesting that these conserved cis-acting elements are sufficient to control the glucose-regulated expression of the amylase gene in the genus Drosophila.

Animals↗
PubMed1984

Cloning of hexokinase isoenzyme PI from Saccharomyces cerevisiae: PI transformants confirm the unique role of hexokinase isoenzyme PII for glucose repression in yeasts.

Hexokinase isoenzyme PI was cloned using a gene pool obtained from a yeast strain having only one functional hexokinase, isoenzyme PI. The gene was characterized using 20 restriction enzymes and located within a region of 2.0 kbp. The PI plasmid strongly hybridized with the PII plasmids isolated previously (Fröhlich et al. 1984). Hence there was a close relationship between the two genes, one of which must have been derived from the other by gene duplication. In contrast, glucose repression was restored only in hexokinase PII transformants; PI transformants remained non-repressible. This observation provided additional evidence for the hypothesis of Entian (1980) that only hexokinase PII is necessary for glucose repression. Furthermore, glucose phosphorylating activity in PI transformants exceeded that of wild-type cells, giving clear evidence that the phosphorylating capacity is not important for glucose repression.

Cloning, Molecular↗
PubMed1978

Catabolite repression in Escherichia coli mutants lacking cyclic AMP.

The regulation of catabolite repression of beta-galactosidase has been studied in Escherichia coli mutants deleted for the adenyl cyclase gene (cya delta), and thus unable to synthesize cyclic AMP. It has been found that, provided a second mutation occurs either in the crp gene coding for the catabolite gene activator protein (CAP) or in the Lactose region, these mutants exhibit catabolite repression. If the catabolite repression seen in the mutant strains corresponds to the mechanism operating in wild-type cells the results would suggest that the intracellular concentration of cyclic AMP cannot be the unique regulator of catabolite repression.

Cyclic AMP↗
PubMed1992

Genetic analysis of serine biosynthesis and glucose repression in yeast.

Serine and glycine biosynthesis in yeast proceed by two pathways: a "glycolytic" pathway, using 3-phosphoglycerate, and a "gluconeogenic" pathway, using glyoxylate. We used a mutation in the cat1 gene to abolish the glucose-repressible "gluconeogenic" pathway and re-isolated two mutants, ser1 and ser2, in the "glycolytic" pathway. The ser1 mutation corresponded to phosphoserine transaminase and ser2 to that of phosphoserine phosphatase. Mutagenesis of a ser1 ser2 cat1 triple mutant facilitated the isolation of a mutation in a new gene, SER10. SER10 appears to be part of a pathway which, under normal growth conditions, is less important in serine biosynthesis. The ser1 ser2 ser10 triple mutants were totally serine auxotrophic on glucose media but serine prototrophic during growth on non-fermentable carbon sources. This phenotype was used to select for possible regulatory mutants that synthesize serine by the gluconeogenic pathway even in the presence of glucose, e.g., with a non-glucose repressible glyoxylate cycle. In an alternative approach to isolate such mutants URA3 and TRP1 expression were placed under the control of the glucose-repressible FBP1 (fructose-1,6-bisphosphatase) promoter. Although both systems resulted in strong selection pressure we could not isolate constitutively derepressed mutants. These results indicate that transcription of glucose-repressible gluconeogenic enzymes is mainly dependent on positive regulatory elements.

Base Sequence↗
PubMed1994

Distinct upstream activation regions for glucose-repressed and derepressed expression of the yeast citrate synthase gene CIT1.

The yeast CIT1 (mitochondrial citrate synthase) gene is subject to glucose repression and is further repressed by glucose plus glutamate. Based on deletion analysis of a CIT1-lacZ gene fusion, DNA sequences between -548 and -273 are required for full expression of CIT1. The region of transcription initiation and the putative TATA element are located at -150 to -100 and -195 respectively. A restriction fragment containing DNA sequences between -457 and -211 conferred activation and glucose-glutamate regulation when placed in either orientation upstream of a UAS-less heterologous yeast gene. Deletion of DNA sequences between -291 and -273 specifically eliminated derepression of CIT1, and destroyed one of two closely-spaced, potential binding sites for the HAP2,3,4 transcriptional activator protein. Ten-base-pair block substitutions in the region -367 to -348 reduced glucose-repressed expression. Thus, it appears that distinct DNA sequences upstream of CIT1 activate expression in glucose-repressed and derepressed cells. Possible mechanisms of regulation by glutamate plus glucose, are discussed.

Amino Acid Sequence↗
PubMed1986

Relationship between sporulation and synthesis of mycobacillin and dipicolinic acid under condition of catabolite repression in Bacillus subtilis.

Sporulation was repressed in the parent strain by various carbon sources whereas glucose-resistant mutants were resistant to them but not to glycerol 2-phosphate. Both mycobacillin and dipicolinic acid synthesis were repressed in the parent by some of the compounds tested, viz. glucose, pyruvate and glycerol 2-phosphate. However, these syntheses in the glucose-resistant mutants were not repressed by glucose and pyruvate but were repressed by glycerol 2-phosphate. The possible interrelationship between sporulation, dipicolinic acid and mycobacillin synthesis is discussed in light of these findings.

Antifungal Agents↗
PubMed2001

Mechanisms of transcriptional repression by the t(8;21)-, t(12;21)-, and inv(16)-encoded fusion proteins.

AML-1 is one of the most frequently translocated genes in human leukemia. AML-1 binds DNA and activates or represses transcription, while the chromosomal translocation fusion proteins in acute myeloid leukemia subvert these functions. The t(8;21) is the second most frequent translocation in acute myeloid leukemia and creates a fusion between the DNA binding domain of AML-1 and the ETO (also known as MTG8) corepressor. The t(12;21) is found in up to 25% of pediatric B cell acute lymphoblastic leukemias and fuses the ETS family transcription factor TEL to the amino terminus of AML-1. In addition, the inv(16), the most frequent translocation in acute myeloid leukemia, fuses the AML-1 cofactor CBFbeta to the smooth muscle myosin heavy chain MYH11. Both the t(8;21) and t(12;21) create transcriptional repressors that impair AML-1 target gene expression. We demonstrated that the fusion proteins encoded by these translocations contact the nuclear hormone corepressors (N-CoR/SMRT), mSin3A, and histone deacetylases. We have also found that both TEL and AML-1 interact with mSin3A. TEL also binds N-CoR and histone deacetylase-3, indicating that wild-type TEL is a transcriptional repressor. The t(12;21) fuses the mSin3A interaction domain of TEL to AML-1 to transform AML-1 from a regulated to an unregulated transcriptional repressor. The recognition that AML-1 interacts with mSin3A to repress transcription suggested that the inv(16) fusion protein might also repress the transcription of AML-1-target genes. In fact, the inv(16) encodes a protein that cooperates with AML-1 to repress transcription. The inv(16) fusion protein was found in a ternary complex with AML-1 and mSin3A, suggesting that the inv(16) also acts by recruiting transcriptional corepressors and histone deacetylases.

3T3 Cells↗
PubMed2003

ScoC mediates catabolite repression of sporulation in Bacillus subtilis.

Sporulation in Bacillus subtilis can be triggered by carbon catabolite limitation. Conversely, carbon source excess can repress the production of extracellular enzymes, motility, and sporulation. Recent studies have implicated a pH-sensing mechanism, involving AbrB, the TCA cycle, Spo0K, and sigmaH in controlling the catabolite repression of sporulation gene expression. In an accompanying paper, we demonstrate that the AbrB-dependent pH-sensing mechanism may not be the only means by which carbon catabolites affect sporulation. In the studies reported here, we have examined the molecular basis underlying the catabolite repression phenotype of mutations in the hpr (scoC), rpoD (crsA47), and spo0A (rvtA11) loci. Loss of function mutations in hpr (scoC) restored sporulation gene expression and sporulation in the presence of excess catabolite(s), suggesting that Hpr (ScoC) has a pivotal role in mediating catabolite repression. Moreover, hpr gene expression increased substantially in the presence of excess catabolite(s), further supporting the involvement of Hpr (ScoC) in the carbon catabolite response system. We suggest that alterations in the phosphorelay response to catabolites may be one mechanism by which catabolite-resistant mutants such as crsA and rvtA are able to sporulate in the presence of excess glucose.

Artificial Gene Fusion↗
PubMed2001

Nitrogen metabolite repression in Hansenda polymorpha: the nmrl-l mutation.

In Hansenula polymorpha, the expression of the nitrate assimilation metabolism is subjected to re-pression-derepression mechanisms triggered by reduced nitrogen compounds such as ammonium. To further our knowledge on the genetics of these regulatory mechanisms, a screening strategy for the isolation of mutants exhibiting nitrate reductase activities in the presence of reduced nitrogen compounds was set up. This strategy makes use of a nitrate+ methylamine mutant to isolate suppressors of its characteristic phenotype--the inability to grow on a nitrate plus methylamine medium. A total of 21 regulatory mutants were isolated with this strategy and grouped into five complementation classes. One of these mutants harbours the recessive mutation nmr1-1, which determines the derepression of the nitrate assimilation metabolism in media containing nitrate plus a repressing nitrogen source (ammonium, methylamine, glutamate, urea or aspartate). Therefore, nitrate reductase activities are detected in the presence of reduced nitrogen sources, as long as nitrate is also in the medium. Our data indicate that the processes of repression-derepression and induction are controlled by elements which are distinct. Furthermore, they indicate that Nmrlp is involved in repressing circuits which control not only the nitrate-utilisation pathway, but also other pathways which are necessary for the utilisation of nitrogen sources alternative to ammonium. Of considerable interest is the fact that our nmr1-1 mutant is derepressed in glutamate but not in glutamine. Since the phenotype of this mutant seems to exclude a glutamine synthetase defect, we suggest that glutamate (or a derivative of this compound) might be involved in signalling nitrogen metabolite repression in H. polymorpha. Thus, in H. polymorpha, a glutamine-dependent circuit may co-exist with a glutamine-independent circuit.

Crosses, Genetic↗
PubMed2003

STA10 repression of STA gene expression is caused by a defective activator, flo8, in Saccharomyces cerevisiae.

The expression of STA genes that encode extracellular glucoamylase isozymes is repressed in most laboratory Saccharomyces cerevisiae strains, which are believed to contain an undefined repressor, designated STA10. To identify the regulator involved in STA10 repression, we investigate the FLO8, MSN1, MSS11, STE12, and TEC1 genes. The Deltaflo8 or Deltamss11 deletion mutants in the sta10 genetic background exhibit both a loss of flocculation ability and a reduction in extracellular glucoamylase activity, as in the STA10 strain. Moreover, the STA10 repression is suppressed completely or partially by the introduction of a single copy of the FLO8 or MSS11 genes. Sequence analysis and complementation testing of the STA10 strain reveal that it has an inactive, mutated flo8-1 allele. A random spore analysis and transplacement (allele replacement) experiment confirms that the repressive phenotype of STA10 is due to the amber mutation of the transcriptional activator, FLO8.

Alleles↗
PubMed1990

Glucocorticoid repression and basal regulation of the epoxide hydrolase promoter.

Through a series of promoter deletions and gene transfer experiments we have examined the basal regulation and glucocorticoid-mediated repression of the rat epoxide hydrolase gene. Three regions of the 5' flanking sequence were found to influence the basal level of promoter function in H4IIE hepatoma cells. Region A (-891 to -355 bp) contains an apparent repressor of epoxide hydrolase expression, while regions B (-271 to -171 bp) and C (-141 to -85) were found to contain important sequences required for optimal promoter activity. Previous work has demonstrated that dexamethasone represses epoxide hydrolase transcription by approximately 50% in isolated rat liver nuclei, and, in this study, we have demonstrated that the ability of the epoxide hydrolase promoter to drive CAT expression is similarly repressed in H4IIE cells treated with 1 microM dexamethasone. Furthermore, the level of endogenous epoxide hydrolase mRNA is decreased by 70-88% in nontransfected H4IIE cells treated with dexamethasone. Interestingly, promoter activity was not decreased by dexamethasone in COS cells, which lack glucocorticoid receptors. The current data show that sequences from -42 to +110 bp are sufficient to support the dexamethasone response, and, furthermore, they suggest that repression may not require direct interaction of the ligand-receptor complex with the promoter region.

Animals↗
PubMed1987

Repression and reactivation of the variant surface glycoprotein gene in Trypanosoma brucei.

Rapid repression of variant surface glycoprotein (VSG) synthesis is an early event during the in vitro transformation of Trypanosoma brucei from coated bloodstream forms to uncoated procyclic cells. Repression occurs at the transcriptional level and is triggered by the combined action of two signals: a reduction in temperature from 37 to 27 degrees C and the addition of the citric acid cycle intermediates citrate and cis-aconitate. It is shown that synthesis of VSG mRNA can be reactivated up to 8 h after triggering differentiation by releasing either one or both of the signals. After 30 h repression is irreversible. The results suggest that transformation of bloodstream forms to procyclic cells proceeds through a reversible phase to an irreversible committed state. A reversible repression of VSG mRNA synthesis is also observed upon inhibition of protein synthesis in bloodstream forms at 37 degrees C.

Aconitic Acid↗
PubMed1990

TPA induces repression of EGF receptor gene expression.

Epidermal growth factor receptor gene expression in response to the tumor promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) was analyzed in the A549 human lung adenocarcinoma cell line using DNA transfection. After 8 h of treatment a definite repression (45%) of EGF receptor gene transcription could be seen. Repression was maintained for up to 24 h. Little or no induction of transcription could be seen prior to the onset of repression for potential enhancer regions both upstream and downstream of the translation start site. The cis-element(s) responsible for repression were localized between residues -384 and -151 of the EGF receptor gene promoter region using a deletion plasmid series.

Cell Line↗
PubMed1991

The repression of the reverse-oriented transcription from the adenovirus terminus by NFI in competition with TFIID.

Nuclear factor I (NF) represses the transcription which is promoted by the cloned adenovirus (Ad) type 5 DNA replication origin and is reverse-oriented with respect to the direction of the replication. The mechanism of this repression by NFI was investigated. In the cell-free transcription system, the repression was observed only when NFI was present during the formation of the transcription initiation complex. From the results of DNase I protection experiments, it was indicated that NFI bound to its binding site in the Ad replication origin prevents TFIID from proper binding to the adjacent AT-rich region and consequently represses the transcription.

Adenoviridae↗
PubMed1994

Autoantigen Ku protein is involved in DNA binding proteins which recognize the U5 repressive element of human T-cell leukemia virus type I long terminal repeat.

We have identified and analyzed a 27-nucleotide sequence (U5 repressive element, designated as U5RE) at the U5 region of the human T-cell leukemia virus type I (HTLV-I) long terminal repeat (LTR) which is required for HTLV-I basal transcriptional repression. The basal promoter strength of constructs that contained deletions in the U5 region of the LTR was analyzed by chloramphenicol acetyltransferase (CAT) assays following transfection of HeLa cells or Jurkat T-cells in the presence or absence of viral transactivator tax protein. We consistently observed a 2- to 5-fold increase in basal promoter activity when sequences between +277 to +306 were deleted. In vivo competition experiments suggested that the U5 DNA fragment from +269 to +295 contains a functional repressive element (U5RE). Using gel mobility shift assays, we have purified a highly enriched fraction that could specifically bind U5RE. This DNA affinity column fraction contained three major detectable proteins on sodium dodecyl sulfate-polyacrylamide gel electrophoresis with silver staining: 110-, 80- and 70-kDa proteins. The 110-kDa protein appeared to be a novel DNA-binding protein whose characteristics are still obscure, while the 70- and 80-kDa proteins were shown to be related to the human autoantigen Ku, the Ku (p70/p80) complex, as demonstrated by amino acid sequencing and immunological analyses. As Ku is known to be involved in transcriptional regulation, the specific interaction of Ku with U5RE raises intriguing possibilities for its function in HTLV-I basal transcriptional repression.

Amino Acid Sequence↗
PubMed1995

Transcriptional repression mediated by the serum response factor.

The serum response element (SRE) contributes to transcriptional repression of the c-fos proto-oncogene. We show that the transcription factor SRF is able to repress SRE-dependent transcription, apparently by sequestering a co-activator. Only the DNA-binding core region is required for this SRE-dependent repression. Furthermore the phosphorylation status at potential casein kinase II sites within an N-terminal repression domain affects SRE-independent transcription. SRF may thus pleiotropically influence cellular transcription, representing a novel aspect of SRF function.

3T3 Cells↗
PubMed1988

Mutational dissection of the HSV-1 immediate-early protein Vmw175 involved in transcriptional transactivation and repression.

Vmw175 is one of five immediate-early (IE) proteins encoded by herpes simplex virus type-1 (HSV-1). It is required for the transcription of later classes of genes and for the accompanying repression of IE expression. Vmw175 has been shown to be a transactivator of transcription and also to autoregulate its own synthesis. We have made a large number of small, in-frame, insertion and deletion mutants of a plasmid-borne copy of the gene encoding Vmw175. Study of the activity of the resultant mutant polypeptides in transient transfection assays has defined the regions of the protein important for the repression of its own promoter, and for the transactivation of an HSV early promoter in synergy with another HSV IE protein, Vmw110. Large stretches of the protein are relatively unimportant for either function, while the regions most sensitive to disruption correlate to sequences conserved between Vmw175 and VZV 140K, the corresponding transactivating protein of Varicella-Zoster virus. The region from amino acids 275 to 490 is particularly important for both repression and transactivation, whereas that from around 840 to 1100 seems to be more important for transactivation than repression. The nuclear localization signal has been mapped to within residues 682-774.

Animals↗